PREDOC2023 (CM)-Understanding the relevance of a new biomarker in the development and prognosis of most common cancers

R-RAS2 belongs to the R-RAS subfamily and is the only GTPase that displayed transforming activities similar to, or even higher than those exhibited by H-, N-, and K-RAS proteins. However, different studies indicated that the RRAS2 gene did not seem to be significantly mutated in human cancer. Instead, RRAS2 has been found overexpressed in the wild-type form at the mRNA and/or protein levels in human cancer, including breast cancer (BC). In order to study if RRAS2 overexpression causes cancer, we have generated a conditional overexpression knock-in mouse line with a RRAS2 construct in the Rosa26 locus to create a line bearing the recombined locus in the germline. In this line, we detected the emergence of chronic lymphocytic leukemia (CLL) in all mice, and breast ductal adenocarcinomas in female mice. On the other hand, the frequent overexpression of RRAS2 mRNA in CLL (80%) and breast cancer (68%) suggests that RRAS2 overpression is behind the development of those cancers. However, perhaps the most compelling support for a genetic linkage between RRAS2 and cancer is the finding of SNP rs8570 in the 3’-UTR of the RRAS2 mRNA which is not found at equilibrium in CLL and BC. Our data place SNP rs8570 as an important biomarker for the identification of the risk of developing BC and its prognosis. In this project we aim to investigate by means of measuring the SNP allele frequencies if RRAS2 is also likely to be involved in other human cancers.